A Study of the Efficacy and Safety of Imatinib Mesylate in Patients With Unresectable or Metastatic Gastrointestinal Stromal Tumors Expressing C-kit Gene

Open, Randomized, Phase II Study of Glivec in Patients With Unresectable or Metastatic Gastrointestinal Stromal Tumors Expressing C-kit Plus 10 Year Extension Study

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00237185

Enrollment

148

Registered

2005-10-12

Start date

2000-06-30

Completion date

2013-06-30

Last updated

2014-08-19

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Unresectable or Metastatic Malignant Gastrointestinal Stromal Tumor (GIST)

Keywords

GIST, c-kit, imatinib mesylate

Brief summary

In the core study, participants with unresectable or metastatic gastrointestinal stromal tumors expressing c-kit were treated with either 400 mg or 600 mg imatinib mesylate for 3 years. The 10 year extension study allowed participants, who successfully completed the core study, to continue study treatment with imatinib mesylate provided they still benefited from treatment and did not demonstrate safety concerns as per the investigator's opinion.

Interventions

DRUGImatinib mesylate

Participants were randomized 1:1 to receive imatinib mesylate 400 mg/day or 600 mg/day. Upon unsatisfactory treatment effect on the starting dose of 400 mg/day or 600 mg/day imatinib mesylate, in the opinion of the treating physician, a dose increase up to 600 mg/day or 800 mg/day, was allowed provided that the participant continued to benefit from the treatment and in the absence of safety concerns.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Men and non-pregnant women ≥18 years of age with the histopathologically documented diagnosis of malignant GIST that was unresectable and/or metastatic. Confirmation of KIT (CD117) expression via immunohistochemical analysis of tumor sample was also required * At least one measurable lesion, as defined by Southwestern Oncology Group (SWOG) Solid Tumor Response Criteria, which had not been previously embolized or irradiated * Performance status ≤3 as defined by the Eastern Cooperative Oncology Group (ECOG) criteria, as well as a life expectancy ≥6 months and adequate end organ function defined as follows: Total bilirubin \<1.5 times upper limit of normal (ULN), aspartate aminotransferase (SGOT) and alanine aminotransferase (SGPT) \<2.5 x ULN (or \<5 x ULN if hepatic metastases were present), creatinine \<1.5 x ULN, absolute neutrophil count (ANC) \>1.5 x 10\^9/L, platelet count \>100 x 10\^9/L

Exclusion criteria

* Patients with fewer than five years of disease-free survival from any other (non-GIST) malignancy except if the other malignancy was not currently clinically significant and did not require active intervention or if the other malignancy was a basal cell skin cancer or a cervical carcinoma in situ * Patients with known brain metastases * Evidence of any of the following disorders: Grade III/IV cardiac failure as defined by the New York Heart Association Criteria, severe concomitant disease, acute or known chronic liver disease (i.e. chronic active hepatitis, cirrhosis) or HIV infection * Chemotherapy or other investigational therapy within four weeks prior to study entry (six weeks for nitrosourea or mitomycin-C) and/or radiotherapy to ≥25% of the bone marrow * Inability to cooperate * Major surgery within two weeks or exposure to other investigational agents within 28 days of entry into the study Other protocol-defined inclusion /

Design outcomes

Primary

Measure	Time frame	Description
Best Tumor Response (Core)	Month 36	Best tumor response was based on the Southwestern Oncology Group (SWOG) criteria. Objective tumor response assessments were categorized according to the following criteria: complete response (CR), partial response (PR), no change or stable disease (SD), progression of disease (PD), unknown where the progression has not been documented and one or more measurable or evaluable sites have not been assessed (UNK), status after resection for progression (RP), status after resection for safety (RS), status after preventive resection (RPR), progressive after first resection (PDR) and not evaluable. Any tumor assessment after surgical resection for preventative reasons was treated like tumor assessments of UNK for calculation of best response. Tumor assessments with current objective status = RP, RS or PDR were treated like assessments with objective tumor status = PD n the calculation of best response.
Best Tumor Response (Core + Extension)	Month 156	Best tumor response was based on the Southwestern Oncology Group (SWOG) criteria. Objective tumor response assessments were categorized according to the following criteria: complete response (CR), partial response (PR), no change or stable disease (SD), progression of disease (PD), unknown where the progression has not been documented and one or more measurable or evaluable sites have not been assessed (UNK), status after resection for progression (RP), status after resection for safety (RS), status after preventive resection (RPR), progressive after first resection (PDR) and not evaluable. Any tumor assessment after surgical resection for preventative reasons was treated like tumor assessments of UNK for calculation of best response. Tumor assessments with current objective status = RP, RS or PDR were treated like assessments with objective tumor status = PD n the calculation of best response.

Secondary

Measure	Time frame	Description
Duration of Response (Core)	Date of confirmed best PR or CR to date of confirmed disease progression during the core period, up to 36 months.	Duration of response was analyzed as time to event for all participants whose best response was at least a PR. The onset of response was the first tumor assessment that was subsequently confirmed to constitute at least a partial best response. The end of response was the first tumor assessment noting PD.
Duration of Response (Core + Extension)	Date of confirmed best PR or CR to date of confirmed disease progression during the core and extension periods, up to 156 months	Duration of response was analyzed as time to event for all participants whose best response was at least a PR. The onset of response was the first tumor assessment that was subsequently confirmed to constitute at least a partial best response. The end of response was the first tumor assessment noting PD.
Progression Free Survival (PFS) (Core + Extension)	Date of first imatinib dose to earliest date of progression, resection due to safety/progression, death due to any cause or discontinuation due to unsatisfactory therapeutic effect during the core and extension periods, up to 156 months.	Progression free survival was analyzed as a time to event for each participant. If a participant had no event, then the PFS was censored at the last tumor assessment.
Time to Treatment Failure (Core)	Date of first imatinib dose to date of earliest occurrence of progression, death due to any cause, or discontinuation from the trial for any reason other than the condition no longer required therapy during the core period, up to 36 months.	Time to treatment failure was analyzed as time to event for all participants. Participants who had neither progressed, died nor discontinued from the trial for any reason other than the condition no longer required therapy were censored for analysis ate the time of their last tumor assessment.
Overall Survival (Core)	Date of first imatinib dose to the date of death during the core period, up to 36 months.	Overall survival was analyzed as time to event for all participants. Participants who did not die were censored at the last date known alive, which is the last date of any study medication, laboratory sample, tumor assessment, adverse event end date or date of last contact.
Time to Onset of Response (Core)	Date of first imatinib dose to the date of the first tumor assessment that was later confirmed to be at least a partial response during the core period, up to 36 months.	Time to response was analyzed as time to event for all participants. Participants who did not meet the definition of confirmed PR/CR were censored at the time of their last progression-free tumor assessment.
Time to Onset of Response (Core + Extension)	Date of first imatinib dose to the date of the first tumor assessment that was later confirmed to be at least a partial response during the core and extension periods, up to 156 months.	Time to response was analyzed as time to event for all participants. Participants who did not meet the definition of confirmed PR/CR were censored at the time of their last progression-free tumor assessment.
Time to Progression (Core + Extension)	Date of first imatinib dose to date of progression or death due to disease indication or discontinuation due to unsatisfactory therapeutic effect during the core and extension periods, up to 156 months.	Time to progression was analyzed as time to event for all participants. Participants who had neither progressed, died nor discontinued from the trial for any reason other than the condition no longer required therapy were censored for analysis at the time of their last tumor assessment.
Time to Treatment Failure (Core + Extension)	Date of first imatinib dose to date of earliest occurrence of progression, death due to any cause, or discontinuation from the trial for any reason other than the condition no longer required therapy during the core and extension periods, up to 156 month.	Time to treatment failure was analyzed as time to event for all participants. Participants who had neither progressed, died nor discontinued from the trial for any reason other than the condition no longer required therapy were censored for analysis at the time of their last tumor assessment.
Overall Survival (Core + Extension)	Date of first imatinib dose to the date of death during the core and extension periods, up to 156 months.	Overall survival was analyzed as time to event for all participants. Participants who did not die were censored at the last date known alive, which is the last date of any study medication, laboratory sample, tumor assessment, adverse event end date or date of last contact.

Countries

Australia, Finland, United States

Participant flow

Participants by arm

Arm	Count
Imatinib Mesylate 400 mg 400 mg Imatinib mesylate	73
Imatinib Mesylate 600 mg 600 mg Imatinib mesylate	74
Total	147

Withdrawals & dropouts

Period	Reason	FG000	FG001
Core	Abnormal laboratory value	0	4
Core	Abnormal test procedure results	1	0
Core	Administrative problems	0	1
Core	Adverse Event	3	4
Core	Death	4	0
Core	Determined ineligible post randomization	1	0
Core	Lack of Efficacy	30	23
Core	Protocol Violation	1	1
Core	Withdrawal by Subject	4	4
Extension	Abnormal laboratory value	0	1
Extension	Administrative problems	1	0
Extension	Adverse Event	1	0
Extension	Condition no longer required study drug	0	1
Extension	Death	1	1
Extension	Lack of Efficacy	9	14
Extension	Lost to Follow-up	1	0
Extension	Withdrawal by Subject	3	2

Baseline characteristics

Characteristic	Imatinib Mesylate 400 mg	Imatinib Mesylate 600 mg	Total
Age, Continuous	56.6 Years STANDARD_DEVIATION 12.9	52.2 Years STANDARD_DEVIATION 11.12	54.4 Years STANDARD_DEVIATION 12.2
Sex: Female, Male Female	29 Participants	35 Participants	64 Participants
Sex: Female, Male Male	44 Participants	39 Participants	83 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	72 / 73	73 / 74
serious Total, serious adverse events	46 / 73	40 / 74

Outcome results

Primary

Best Tumor Response (Core)

Best tumor response was based on the Southwestern Oncology Group (SWOG) criteria. Objective tumor response assessments were categorized according to the following criteria: complete response (CR), partial response (PR), no change or stable disease (SD), progression of disease (PD), unknown where the progression has not been documented and one or more measurable or evaluable sites have not been assessed (UNK), status after resection for progression (RP), status after resection for safety (RS), status after preventive resection (RPR), progressive after first resection (PDR) and not evaluable. Any tumor assessment after surgical resection for preventative reasons was treated like tumor assessments of UNK for calculation of best response. Tumor assessments with current objective status = RP, RS or PDR were treated like assessments with objective tumor status = PD n the calculation of best response.

Time frame: Month 36

Population: Treatment population: The treatment population included all randomized participants who received at least one dose of study medication.

Arm	Measure	Group	Value (NUMBER)
Imatinib Mesylate 400 mg	Best Tumor Response (Core)	Complete response	0 participants
Imatinib Mesylate 400 mg	Best Tumor Response (Core)	Partial response	49 participants
Imatinib Mesylate 400 mg	Best Tumor Response (Core)	Stable disease	10 participants
Imatinib Mesylate 400 mg	Best Tumor Response (Core)	Progressive disease	12 participants
Imatinib Mesylate 400 mg	Best Tumor Response (Core)	Not evaluable	2 participants
Imatinib Mesylate 400 mg	Best Tumor Response (Core)	Unknown	0 participants
Imatinib Mesylate 600 mg	Best Tumor Response (Core)	Not evaluable	3 participants
Imatinib Mesylate 600 mg	Best Tumor Response (Core)	Complete response	1 participants
Imatinib Mesylate 600 mg	Best Tumor Response (Core)	Progressive disease	6 participants
Imatinib Mesylate 600 mg	Best Tumor Response (Core)	Partial response	49 participants
Imatinib Mesylate 600 mg	Best Tumor Response (Core)	Unknown	2 participants
Imatinib Mesylate 600 mg	Best Tumor Response (Core)	Stable disease	13 participants

Primary

Best Tumor Response (Core + Extension)

Time frame: Month 156

Population: Treatment population: the treatment population included all participants who had at least one dose of study medication.

Arm	Measure	Group	Value (NUMBER)
Imatinib Mesylate 400 mg	Best Tumor Response (Core + Extension)	Complete response	1 participants
Imatinib Mesylate 400 mg	Best Tumor Response (Core + Extension)	Partial response	49 participants
Imatinib Mesylate 400 mg	Best Tumor Response (Core + Extension)	Stable disease	10 participants
Imatinib Mesylate 400 mg	Best Tumor Response (Core + Extension)	Progressive disease	11 participants
Imatinib Mesylate 400 mg	Best Tumor Response (Core + Extension)	Not evaluable	2 participants
Imatinib Mesylate 400 mg	Best Tumor Response (Core + Extension)	Unknown	0 participants
Imatinib Mesylate 600 mg	Best Tumor Response (Core + Extension)	Not evaluable	3 participants
Imatinib Mesylate 600 mg	Best Tumor Response (Core + Extension)	Complete response	2 participants
Imatinib Mesylate 600 mg	Best Tumor Response (Core + Extension)	Progressive disease	6 participants
Imatinib Mesylate 600 mg	Best Tumor Response (Core + Extension)	Partial response	48 participants
Imatinib Mesylate 600 mg	Best Tumor Response (Core + Extension)	Unknown	2 participants
Imatinib Mesylate 600 mg	Best Tumor Response (Core + Extension)	Stable disease	13 participants

Secondary

Duration of Response (Core)

Duration of response was analyzed as time to event for all participants whose best response was at least a PR. The onset of response was the first tumor assessment that was subsequently confirmed to constitute at least a partial best response. The end of response was the first tumor assessment noting PD.

Time frame: Date of confirmed best PR or CR to date of confirmed disease progression during the core period, up to 36 months.

Population: Treatment population: the treatment population included all participants who had at least one dose of study medication and whose best response was at least a PR.

Arm	Measure	Value (MEDIAN)
Imatinib Mesylate 400 mg	Duration of Response (Core)	113 weeks
Imatinib Mesylate 600 mg	Duration of Response (Core)	123 weeks

Secondary

Duration of Response (Core + Extension)

Time frame: Date of confirmed best PR or CR to date of confirmed disease progression during the core and extension periods, up to 156 months

Population: Treatment population: the treatment population included all participants who had at least one dose of study medication and whose best response was at least a PR.

Arm	Measure	Value (MEDIAN)
Imatinib Mesylate 400 mg	Duration of Response (Core + Extension)	27 months
Imatinib Mesylate 600 mg	Duration of Response (Core + Extension)	30 months

Secondary

Overall Survival (Core)

Overall survival was analyzed as time to event for all participants. Participants who did not die were censored at the last date known alive, which is the last date of any study medication, laboratory sample, tumor assessment, adverse event end date or date of last contact.

Time frame: Date of first imatinib dose to the date of death during the core period, up to 36 months.

Population: Treatment population: the treatment population included all participants who had at least one dose of study medication.

Arm	Measure	Value (MEDIAN)
Imatinib Mesylate 400 mg	Overall Survival (Core)	NA months
Imatinib Mesylate 600 mg	Overall Survival (Core)	NA months

Secondary

Overall Survival (Core + Extension)

Time frame: Date of first imatinib dose to the date of death during the core and extension periods, up to 156 months.

Population: Treatment population: the treatment population included all participants who had at least one dose of study medication.

Arm	Measure	Value (MEDIAN)
Imatinib Mesylate 400 mg	Overall Survival (Core + Extension)	55.9 months
Imatinib Mesylate 600 mg	Overall Survival (Core + Extension)	57.1 months

Secondary

Progression Free Survival (PFS) (Core + Extension)

Progression free survival was analyzed as a time to event for each participant. If a participant had no event, then the PFS was censored at the last tumor assessment.

Time frame: Date of first imatinib dose to earliest date of progression, resection due to safety/progression, death due to any cause or discontinuation due to unsatisfactory therapeutic effect during the core and extension periods, up to 156 months.

Population: Treatment population: the treatment population included all participants who had at least one dose of study medication.

Arm	Measure	Value (MEDIAN)
Imatinib Mesylate 400 mg	Progression Free Survival (PFS) (Core + Extension)	19.3 months
Imatinib Mesylate 600 mg	Progression Free Survival (PFS) (Core + Extension)	25.2 months

Secondary

Time to Onset of Response (Core)

Time to response was analyzed as time to event for all participants. Participants who did not meet the definition of confirmed PR/CR were censored at the time of their last progression-free tumor assessment.

Time frame: Date of first imatinib dose to the date of the first tumor assessment that was later confirmed to be at least a partial response during the core period, up to 36 months.